CZ115597A3 - Beta, beta dihydroxy mes-substituted chlorines, isobacteriochlorines, bacteriochlorines and processes for preparing thereof from beta, beta unsubstituted tetrapyrrole macrocycles - Google Patents

Abstract

A beta , beta '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin compound having the formula (I) or (II): <IMAGE> (I) or <IMAGE> (II) wherein M is a metal. A novel method for synthesizing the compound of formula (I) or (II) comprises the steps of: a. osmylating a beta . beta '-unsubstituted, meso-substituted porphyrin to form an osmate ester at the beta , beta '-position, and b. reducing the osmate ester to form the corresponding beta , beta '-dihydroxy meso-substituted chlorin, bacteriochlorin or isobacteriochlorin of formula (I) or (II).

Description

Technical field

The invention relates to certain dihydroxychlorine, bacteriochlorine or isobacteriochlorine compounds and their preparation. In particular, the invention relates to dihydroxylation of β, β '-substituted tetrapyrrole macrocycles, which are already substituted in some or all of the meso-positions by an alkyl group or an aromatic ring. Many of these compounds can be used as photosensitizers in the field of photodynamic therapy (PDT) to target radiation destruction to unwanted cells, tissues or other unwanted matter.

BACKGROUND OF THE INVENTION

It is already known in the PDT art that many tetrapyrrole macrocycles, such as purpurines, chlorines, bacteriochlorines, phthalocyanines, and benzochlorines, have the ability to accumulate at the tumor site and absorb light, switching to an activated state depending on light. These macrocycles then exhibit a cytotoxic effect on cells or other tissues in which they accumulate when irradiated at a suitable wavelength.

However, in order to achieve the desired phototoxic effect deep within the target tissue, photosensitizers have to be used which have a high absorption coefficient at wavelengths above 650 nm, which is the area in which light passes best through body tissues. Here you can refer to the publication:

Sternberg et al., An OverView of Second Generation Drugs for Photodynamic Therapy Including BPD-MA (Benzoporphyrin Derivative), in Photodynamic and Biomedical Lasers. pp. 470-474 (Spineli et al. eds. 1992).

By reducing the porphyrin, chlorine (i.e., dihydroporphyrin) is formed, with optical properties changing in this desirable direction. Further reduction of the chlorine produces bacterichlorin (i.e. tetrahydroporphyrin), thereby further enhancing the desired effect. To date, only one method of converting mesotetrafenylorphyrines to the corresponding chlorines is the diimide reduction described in Vitlock et al., Diimide Reduction of Porfyrins, J, Am, Chem. Soc., 91, 7485-89 (1969). In this work, however, the product of preparation is not a β, β-dihydroxy-substituted derivative.

In addition to the suitable light absorption properties of chlorines and bacteriochlorines, the amphiphilic character of these compounds, potentially suitable for the biodistribution of the active substance, has been pointed out. For example, in Bonett et al., Second Generation Tumor Photosensitisers: The Synthesis and Biological Activity of Octaalkyl Chlorines and Bacterichlorins with Graded Amphiphilic Character, in J. Chem. Soc., Perkin Trans 1: 1465-1470 (1992), proposes the use of meso-tetra (hydroxyphenyl) chlorines and their corresponding bacterichlorines as photosensitizers in PDT.

It is known that J-substituted porphyrins can be oxidized by the action of osmium tetroxide (OsO ^) on one or more double bonds to form the β, β'-position an ester ester, which can then be reduced by some of the many reducing agents to the corresponding vicinal diol . For example, see Chang et al., A Novel Method of Functionalizing the Ethyl Chain of

Octaethylporphyrin, in J. Org. Chem. 52, pp. 926-929, the corresponding diol was obtained by oxidation of octaethylporphyrin with OSO ₄ in the presence of pyridine.

Osmylation of fully phenyl) porphyrin The procedure of β, β-alkyl substituted 5,15-bis- (methyl provided analogously to the diol) See also Osuka et al., Synthesis of

5,15-Diaryl-Substituted Oxochlorins from 5,15-Diaryl-octylporphyrin, in Bull. Chem. Soc. Jap., 66, pp. 3837-3839 (1993).

However, the diols thus obtained have a tendency to pinacol-pinacolone rearrangement when exposed to acidic conditions to form oxochlorines, as shown below:

When investigating the ability of the substituents, it has been found that hydrogen has the greatest tendency to migrate when switching the J-monosubstituted diols. Reference is made here to Chang et al. Migratory ApII ^{u es} in Pinacol Rearrengement of individual vícmigrace

Dihydroxychlorins, in J. Heterocyclic Chem., 22, p

1741 (1985).

Vicinal dihydroxy chlorines have already been obtained from β, β'-alkyl substituted porphyrins by oxidation of osmium tetroxide in pyridine, confirming that the product is subject to pinacolonic rearrangement by sulfuric acid. See Bonett et al., The Oxidation of Porphyrins with Hydrogen Peroxide in Sulfuric Acid, in Proc. Chem. Soc., 371-72 (1964) and Chang et al., Differentiation of

Bacteriochlorin and Isobakteriochlorin Formation by Metalation. High Yeald Synthesis of Porfyrindiones via OsO ₄ Oxidation, in J. Chem. Soc. Chem. Commun., 1213-15 (1986).

However, it has not been reported that the dihydroxyosmylation product of β, β'-unsubstituted, meso-substituted porphyrins is stable in the sense that it does not undergo analogous rearrangement.

Further, if the starting porphyrin carries a J-substituted structure that reduces the overall symmetry of the molecule, then dihydroxylation results in a non-static mixture of stereo- and regioisomers. For example, by osmylation of deuteroporphyrin-IX dimethyl ester, a mixture of the following regioisomers and their corresponding stereoisomers is obtained. Chang et al., C-Hydroxy- and C-Methylchlorines may be incorporated herein by reference. A Convenient Routes to Heme d and Bonellin Model Compounds, in J. Org. Chem., 50, pp. 4989-4991 (1985).

The following is a diagram indicating the formation of said isomers in said reaction.

Even under the best conditions, separation of these regioisomers and stereoisomers is difficult.

Now, the meso-substituted β, β hyd -dihydroxylated to give the vic-diol, as shown in the reaction scheme:

ascertained by the porphyrinic action of OsO, that the β, β'-unsubstituted compounds can be shown in the following

1.OsO ₄ / pyridine 2.reduction

The resulting meso-substituted vic-diols are unexpectedly stable. It is surprising that their dehydration and rearrangement occur only under relatively harsh conditions, such as refluxing with benzene containing a catalytic amount of HCIO4. This is unexpected since the high migration ability of J-hydrogen atoms is known and, moreover, the expected tendency of the molecule to eliminate water, which results in the disintegration of a fully conjugated porphyrin resonance structure as an enolic tautomer, is shown below. Crossley et al., Tautomerism in 2-Hydroxy-5,10,15,20-tetraphenylporphyrin: An Equilibrium Betveen Enol, Keto, and Aromatic Hydroxyl Tautomers, in J. Org. Chem., 53, 1132-1137 (1988).

Such meso-phenyl oxoporphyrins have already been prepared in a substantially different way. See, eg, Catalano et al., Efficient Synthesis of 2-Oxy-5,10,15,20-tetraphenylporphyrins from a nitroporphyrin by Novel Multi-Step Cine-substitution Sequence, J, Chem, Soc. Commun., 1537-38 (1984).

It has been found that when hydroxy groups are added to a pre-attached meso substituent, for example to phenyl groups in meso-tetra (hydroxyphenyl) -porphyrins, -chlorines and bacteriochlorines, they may be effective as active PDT agents. See Berenbaum et al., Meso-Tetra (hydroxyphenyl) -porphyrins, and New Class of Potent Tumor Photosensitisers with Favourable Selectivity, Br. J. Cancer, 54, 717-25 (1986) and Ris et al.,

Photodynamic Therapy with m-Tetrahydroxyphenyl Chlorine in vivo: Optimization of the Therapeutic Index, Int. J. Cancer. 55: 245-49 (1993). By introducing the hydroxy groups at the J-positions and residues not only a new class of compounds with photosensitizing activity has been found, it can also reasonably be assumed that the photosensitizers of the invention are even better than the known compounds because their molecules are more amphiphilic.

Furthermore, in β, β'-dihydroxylation, the high symmetry of the molecules of the starting materials causes the formation of only one regioa stereoisomer of the resulting chlorine. For example, dihydroxylation of meso-tetrafenylporphyrin provides only one isomer of β, β'-dihydroxy-meso-tetra phenylbacteriochlorine. Further, the subsequent β, β'-dihydroxylation of β, β'-dihydroxychlorine provides only two, easily separable diastereomers of the tetrahydroxy-bacteriochlorine product. This remarkable reduction of isomers solves a process for obtaining PDT reagents that has a high yield and is of great practical, economic and medical importance.

For example, Vitlock et al. , Diimide Reduction 91, 7485-89 (1969);

Bacteriochlorin and of Porphyrins, J. Am. Chem. Soc., Chang et al. Differentiation of by

Isobakteriochlorin Formation

Metallation: High Yeald Synthesis of Porfyrindiones via OsO Oxidation, J. Chem. Soc., Chem. Comm., 1213-15 (1986), and the fact that J-hydroxylation of β, β'-dihydroxychlorines (and the reduction reaction of diimides with β, β'-dihydroxychlorines or, in this case, β, β'-dihydroxylation of tetrafenylchlorines) are reactions capable of accentuating the metal-directing effect.

Osmylation / reduction of the metalochlorines provides a metallo-iso-bacteriochlorin chromophore from which the basic isobacteriochlorin chromophore can be obtained by demetalate. In contrast, osmylation / reduction of the free chlorine base provides the corresponding bacteriochlorin chromophores.

A further advantage is that the meso substituent can be further substituted in many ways, especially when it is an aryl ring, such as a phenyl group. Thus, the hydroxylation of β, β'-unsubstituted, meso-substituted porphyrins and chlorines by oxidation of OsO ^ and subsequent reduction of the intermediate (ester osmiate formed in β, β'-position) can produce a number of analogous vic-diol substituted chlorines and bacterichlorines exhibiting extremely useful properties as PDT reagents as they amplify and bathochromically shift the Q bands and increase the amphiphilic character. Furthermore, due to the possibility of further substitution of the meso-substituents as such, there is a possibility of fine-tuning the pharmacokinetic and dynamic properties of the compounds to a much greater extent.

SUMMARY OF THE INVENTION

According to the present invention, β, β'-dihydroxy mesosubstituted chlorine and isobacteriochlorine (I) or (II):

new chlorinated and bacterio compounds of the general formula were prepared

or

wherein: M is a metal selected from the group of Cu (II), Zn (II), Fe (III) Cl, Sn, Mn (III), Gd (IIl), In and Tc which consists of Ni (II), Ge , Si, Ga, Al,

A is a circle that has the structure:

D is a ring having the structure:

R 8 to R 8 are independently hydrogen, a lower alkyl group, a lower alkylcarboxylic acid esterified acid group, a keto, hydroxy, nitro, amino, or a group linked to another ring, ring substituent or meso-substituent to form a linked 5- or 6-membered ring and up to H, substituted or unsubstituted alkyl groups or substituted or unsubstituted aromatic rings, which may be the same or different, provided that at least one general symbol up to does not represent H.

Furthermore, a method for the efficient synthesis of compounds of formulas (I) and (II) has been invented.

a. osmylation of the mesosubstituted metalloporphyrin of formula (III):

wherein A, D, R and R ₆ and S ¹ AZS ⁴ are described above, treating said osmate ester to form an ester of β, β'-position, and

b. reduction of the ester osmiates to give the corresponding β, β'-dihydroxy meso-substituted chlorine, bacteriochlorin or isobacteriochlorin of formula (I).

Three methods are provided for the demethylation of compounds of formula (II). The first includes the following stages:

a. osmylation of the mesosubstituted metalloporphyrin of formula (III) to form an β, β-β-ester ester;

b. reduction of an ester osmiate, wherein the ester osmiate is converted to the corresponding β, β-dihydroxy mesosubstituted chlorine, bacteriochlorin or isobacteriochlorin of formula (I) and meso-substituted isobacteriochlorine to form meso-substituted isobacteriochlorine demetation of β, β-dihydrochloride bacteriochlorin or formula (I) from the reduction step, demethylated β, β'-dihydroxy chlorine, bacteriochlorin or formula (II).

The second process for producing the demetallized compounds of formula (II) comprises the following steps:

a. an osmylation of the mesosubstituted metalloporphyrin of formula (III) to form an eighth ester in the β, β 'position;

b. disassembly of ester osmates; and

c. reduction of the demetalized ester osmate, wherein the ester osmate is converted to the corresponding β, β'-dihydroxy meso-substituted chlorine or bacteriochlorin of formula (II).

A third process for producing a demethylated compound of formula (II) comprises the following steps:

a. osmylation of a meso-substituted porphyrinogen compound of formula (IV):

where A, D, to <5 and S ¹ to S4 are as defined above to form an δ, β, β-ester ester,

b. reduction of the obtained ester osmate, wherein the ester osmate is converted to the corresponding β, β'-dihydroxy meso-substituted chlorine or bacteriochlorine of formula (II).

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further elucidated with reference to the following drawings, in which:

Giant. 1 represents the UV-Vis spectrum of 2,3-vic-dihydroxytetrafenyl chlorine (continuous curve) and the UV-Vis spectrum of [2,3-more-dihydroxy-tetrafenylchlorinate] zinc (II) (dashed curve).

Giant. 2 represents the UV-Vis spectrum of 2,3-vic-dihydroxy-14-tetrafenylbacteriochlorine.

Giant. 3 shows the UV-Vis spectrum of the 2,3,12,13-tetrahydroxy-tetrafenylbacteriochlorin-E-isomer (solid line) and the UV-Vis spectrum of the 2,3,12,13-tetrahydroxy-tetrafenylbacteriochlorin-Z-isomer (dashed line).

Giant. 4 shows the UV-Vis spectrum of the [7,8-vic-dihydroxytetrafenylisobacteriochlorinate] zinc (II) E-isomer.

Figure 5 shows the UV-Vis spectrum of 2,3,7,8-vic-tetrahydroxytetrafenylisobacteriochlorin-E-isomer (solid line) and [2,3,7,8-vic-tetrahydroxytetrafenylisobacteriochlorinate] zinc (II) E-isomer (intermittent) line).

DETAILED DESCRIPTION OF THE INVENTION The β, β-dihydroxy-substituted-chlorine, bacteriochlorine or isobacteriochlorine compounds of the invention have formulas (I) and (II) as described and illustrated above. M may be a metal of any kind capable of forming a complex of formula (I), but is preferably selected from the group consisting of Ni (II), Cu (II), Zn, Sn, Ge, Si, Ga, and Al. An important property of the selected metal is that it can be introduced into the porphyrin structure, but also that it can be removed from the chlorine resulting from the process of the invention.

And it can mean any circle with the following structure:

D can be any ring with the following structure:

N or

HIM

HIM

N

It is to be understood that all the corresponding resonant forms of the structures shown above also fall within the scope of the meanings of terms A and D. Preferably, however, at least one of rings A and D is identical to rings B and C. Even more preferably, they are rings A and D identical to rings B and C together with them form a porphyrin core structure which then contains four identical rings, all of which are joined by a bridged carbon atom as described at the meso-position.

R 1 to R 8 may be any of a number of cyclic substituents as long as they do not interfere with the osmylation and reduction carried out in the steps described above. Preferably, R 1 to R 8 are independently hydrogen, lower alkyl such as methyl, ethyl, n-propyl, isopropyl, t-butyl and n-pentyl, further lower alkyl carboxylic acid such as formyl, carboxymethyl, carboxyethyl, carboxy-n- butyl, carboxy-secbutyl and carboxy-n-hexyl, further a group of esterified carboxylic acid such as -CH ₂ CH ₂ COOCH ₃ , -CH ₂ CH ₂ COOCH ₂ CH ₃ , -ch ₂ ch (ch ₃ ) cooch ₂ ch ₃ , -CH ₂ CH ₂ CH ₂ COOCH ₂ CH ₂ CH ₃

-CH ₂ CH (CH ₃ ) ₂ COOCH ₂ CH ₃ , keto, hydroxy, nitro, amino, or the like

Further, and R ₂ , R ₃ and R ₄ , or R ₅ and R 8 may be taken together with another ring, ring substituent or meso substituent to form a closed 5- or 6-membered ring. The closed 5- or 6-membered ring may be a saturated or unsaturated, carbocyclic or heterocyclic, 5 or 6-membered ring that does not interfere with the osmylation and reduction reaction steps of the invention. Examples of such rings may be cyclopentane, furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole,

1,2-dithiol, 1,2,3-oxathiol, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiathiazole, 1,2,4-oxadiazole,

1,2.5-oxadiazole, 1,3-oxathiol, benzene, cyclohexane, 1,2-pyran,

1,4-pyran, 1,2, -pyrone, 1,2-dioxin, 1,3-dioxin (dihydroform), pyridine, pyridazine, pyrimidine, pyrazine, piperazine,

1,3,5-triazine, 1,2,4-triazine, 1,2,4-oxazine, 1,3,2-oxazine, o-isoxazine, 1,2,5-oxathiazine, 1,4-oxazine, p- isoxazine,

1,2,6-oxathiazine, 1,3,5,2-oxadiazine, morpholine, azepine, oxepine, thiepine, 1,2,4-diazepine, and the like. Preferably, the ring that together R 1 and R ₂ , R 8 and R 8, or R 8 and R 8 is six-membered. More preferably, the ring is a carbocyclic ring, i.e. a benzene ring.

In a particular preferred embodiment, R 1 to R 8 are independently hydrogen, methyl, ethyl or lower alkyl esters, most preferably hydrogen, methyl or ethyl.

S ¹ to are the same or different and can be H, any of a large number of substituted or unsubstituted alkyl groups, any of substituted or unsubstituted cycloalkyl groups, and aromatic rings. When one or more substituents is an alkyl group, it preferably has 1 to 18 carbon atoms, more preferably 1 to 12 carbon atoms, and even more preferably up to 6 carbon atoms. Examples of typical alkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, n-pentyl and n-octyl.

When one or more of the radicals S ¹ to S ^{4 is} an alkyl group, it may be unsubstituted or substituted, and its substituent may be one of the groups which do not interfere with the osmylation or reduction reactions carried out according to the invention and which are described here. Thus, for example, if one or more of the radicals S ¹ to S ^{4 is an} alkyl group, this group may be substituted by a halogen atom such as fluorine, chlorine or bromine, by a hydroxy group such as pentoses and hexoses, by a thiol or carbonyl group an aldehyde, ketone or carboxylic acid (e.g., fatty acid) or ester or amide, further may be substituted with a primary, secondary, tertiary or quaternary amino group, nitrile group, phosphate group, sulfonate group, and the like.

When S ¹ to S ^{4 is a} cycloalkyl group, it may preferably contain 3 to 7 carbon atoms. Examples of typical cycloalkyl groups are cyclopropyl, cyclohexyl and cycloheteroalkyl such as glucopyranose and fructopyranose sugars. When S ¹ to S ^{4 is a} cycloalkyl group, it may be substituted or unsubstituted by any group that does not interfere with the osmylation or reduction reactions. For example, when S ¹ to S ^{4 is a} cycloalkyl group, it may be substituted by one of the same substituents as mentioned above in case any one of the S ¹ to S ⁴ substituents is an alkyl group.

When one or more of the S ¹ to S ⁴ substituents is an aryl group, it preferably contains from about 5 to about 12 carbon atoms, optionally contains one or more heteroatoms, and optionally also may contain rings which are linked to an existing conjugated porphyrin ring structure. Examples of such rings are furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole,

1,2-dithiol, 1,3-dithiol, thiazole, isothiazole,

1.2.5- oxadiazole,

1.2.3.5- oxatriazole,

1.3.2-dioxazole,

1,2,3-oxathiol, isoxazole, oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,

1,3,4-oxadiazole, 1,2,3, 4-oxatriazole,

1,2,3-dioxazole, 1,2,4-dioxazole,

1,2,5-oxathiazole,

1,3,4-dioxazole,

1,3-oxathiol, benzene, 1,2-pyran, 1,4-pyran, 1,2-pyron,

1,4-pyron, 1,2-dioxin, 1,3-dioxin, pyridine,

N-alkylpyridinium, pyridazine, pyrimidine,

1,3,5-triazone, 1,2,4-triazine,

1,3,2-oxazine, p-isoxazine, pyrazine, 1,2,3-triazine, 1,2,4-oxazine, 1,4-oxazine, o-isoxazine, 1,2,6-oxathiazine, 1, 4,2azepine, oxepine, thiepine,

1,3,6-oxazine,

1,2,5-oxathiazine, oxadiazine, 1,3,5,2-oxadiazine,

1,2,4-diazepine, indene, isoindene, benzofuran, isobenzofuran, thionaphthalene, isothionaphthalene, indole, indolenine,

2-isobenzazole, 1,4-pyridine, pyrando [3,4-b] -pyrrole, isoindazole, indoxazine, benzoxazole, anthranil, naphthalene, 1,2-benzopyran,

1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone,

2,3-benzopyrone, quinoline, isoquinoline, 1,2-benzodiazine, naphthyridine, pyrido [3,4-b] pyridine, pyridopyrido [4,3-b] pyridine, 1,3,2-benzoxazine, 2,3, 1-benzoxazine, 3,1,4-benzoxazine,

1,4-benzisoxazine, anthracene, phenanthrene,

1,3-benzodiazine, [3,2-b] pyridine,

1.4.2- benzoxazine,

1,2-benzisoxazine, carbazole, and the like, xanthene, acridine, purine, steroid compounds

In a particularly preferred embodiment, the substituents indicated by S ¹ to S ^{4 are} selected from the group consisting of phenyl, naphthyl, pyridinyl and lower N-alkyl pyridinium salts. Even more preferred is an embodiment in which the substituents S ¹ to S ^{4 are} identical.

The substituents of the ^{invention have at least one of 2} S having the following structure:

or 2'-N

wherein X, Y, Z, X ', Y', and Z 'are a plurality of substituents and are fine tuning and conditioning can be any of a large generally used for fine biological activity, biodistribution, absorption of other product properties, including physical, and their dependence on various influences . One way in which this fine-tuning can be performed is by the way that the compound of the formula molecule. By amphiphilic asymmetric, the choice of substituents by such (I) or (II) is amphiphilic means a more water-soluble molecule whose molecule has:

(1) (a) a highly polar, regionally, and also this molecule has (b) a highly hydrophobic, water-insoluble region, or whose molecule has:

(2) (a) a non-ionic region as well as (b) an ionic region.

However, it should be noted that the invention also encompasses β, β'-dihydroxy meso-substituted chlorine, bacteriochlorine or isobacteriochlorine compounds having substantially or exactly identical aryl substituents. Further, any substituent selected should not adversely affect the ability of the compounds to react according to step a and step b, which are used to prepare the compounds of the invention.

The substituents X, Y, Z, X ', Y' and Z 'are preferably: (1) a hydrogen atom, (2) a halogen such as fluorine, chlorine, iodine and bromine, (3) a lower alkyl group such as methyl (4) a lower alkoxy group such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like, (5) hydroxy, (6) ) carboxylic acids or salts thereof such as -CH ₂ COOH, -CH ₂ COONa ⁺ , -CH ₂ CH (Br) COOH, -CH ₂ CH (CH 3) COOH, -CH (Cl) -CH 2 -CH (CH 3) -COOH, -CH 2 - CH2C (CH3) 2-COOH, -CH2-CH2 C (CH3) 2-COO "K ^+, -CH 2 -CH ₂ -CH ₂ -CH ₂ - COOH, C _{(CH3) 3} -COOH,

CH (Cl ₂ ) -COOH, and the like, (7) carboxylic acid esters such as -CH ₂ CH ₂ COOCH ₃ , -CH ₂ CH ₂ COOCH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) COOCH ₂ CH ₃ -CH ₂ CH ₂ CH ₂ COOCH ₂ - CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ COOCH ₂ CH ₃ and the like, (8) sulfonic acids or salts thereof, for example Group I and Group II salts, ammonium salts and organic cation salts such as quaternary ammonium salts, (9) sulfonic acid esters such as methylsulfonate, ethylsulfonate, cyclohexylsulfonate and the like, (10) amino groups such as primary unsubstituted amino, methylamino, ethylamino, n-propylamino, isopropylamino, 5-butylamino , sec-butylamino, dimethylamino, trimethylamino, diethylamino, triethylamino, di-n-propylamino, methylethylamino, dimethyl-sec-butylamino,

2-aminoethyloxy, ethylenediamino, 2- (N-methylamino) heptyl, cyclohexylamino, benzylamino, phenylethylamino, anilino,

N-methylanilino, N, N-dimethylanilino, N-methyl-Nethylanilino,

3,5-dibromo-4-anilino, p-toluidinyl, diphenylamino, 4,4'-dinitrodiphenylamino and the like, (11) cyano, (12) nitro, (13) biologically active group or (14) any other substituent, amphiphilic the nature of compound (1) or (II).

The term biologically active moiety can be any moiety that selectively promotes accumulation, elimination, the amount of bound substances, or bond strength, particularly in a biological environment. For example, one category of biologically active groups is a substituent selected from sugars, namely: (1) aldoses such as glyceraldehyde, erythrosa, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose and talosa ; (2) ketoses such as hydroxyacetone, erythrulose, rebulose, xylulose, psicose, fructose, sorbose, and tagatose; (3) pyranoses such as glucopyranose; (4) furanoses such as fructofuranose; (5) O-acyl derivatives such as penta-O-acetyl-1-glucose; (6) O-methyl derivatives such as methyl I-glucoside, methyl J-glucoside, methyl-1-glucopyranoside and methyl-2,3,4,6-tetra-O-methyl-glucopyranoside; (7) phenylosazones such as glucophenylosazone; (8) sugar alcohols such as sorbitol, mannitol, glycerol, and myo-inositol; (9) sugars such as gluconic acid, glucaric acid and glucuronic acid, L-gluconolactone, L-glucuronolactone, ascorbic acid, and dehydroascorbic acid; (10) phosphoric acid esters such as 1-phosphoric acid 1-glucosan, 6-phosphoric acid 1-glucosine, 1,6-diphosphoric acid 1-fructosan, and 6-phosphoric acid I-fructosan; (11) deoxy sugars such as 2-deoxy-ribose, rhamnose (deoxy-mannose), and fucose (6-deoxy-galactose); (12) amino sugars such as glucosamine and galactosamine; muramic acid and neuraminic acid; (13) disaccharides such as maltose, sucrose and trehalose; (14) trisaccharides such as raffinose (fructose, glucose, galactose) and melezitose (glucose, fructose, glucose); (15) polysaccharides (glycans) such as glucans and mannans; and (16) storage polysaccharides such as 1-amylose, amylopectin, dextrins and dextrans.

Also useful as biologically active ingredients are amino acid derivatives such as those derived from valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid, glycine, histidine, proline , lilac, tyrosine, asparagine, and glutamine. Also useful are peptides, especially those having known affinity for specific receptors, for example oxytocin, vasopressin, bradykinin, LHRH, thrombin and the like.

Another useful group of substituents are those such as adenosine, guanosine, and 2'-deoxyribonucleosides such as

2'-deoxyguanosine, 2'-deoxycytidine and biologically active derived from nucleosides, cytidine and uridine; is 2'-deoxyadenosine,

2'-deoxythymidine.

Another category of biologically active moieties that are particularly useful is any of the ligands that are specific for a particular biological receptor. The term receptor-specific ligand refers to a moiety that carries a cell surface receptor, and thus includes contours and specific templates that are complementary to the contours and templates of a particular biological receptor. The ligand is not itself a receptor, but is a substance that is complementary to the receptor. It is easy to understand that a wide variety of cell types have specific receptors designed to carry hormones, growth factors, neurotransmitters. Thus, although such specific receptor-specific ligands are known and explainable, a receptor-specific ligand herein means any substance, natural or synthetic, that specifically binds to the receptor.

Examples of such receptors are: (1) steroid hormones such as progesterone, estrogens, androgens and adrenaline corticoid hormones, (2) growth factors such as epidermal growth factor, nerve growth factor, fibroblast growth factor and the like, (3) other protein hormones such as human growth hormone, parathyroid hormone and the like; and (4) neurotrasmitters such as acetylcholine, serotonin, dopamine and the like. Any analog of these agents that can also successfully bind to a biological receptor also belongs to this.

Particularly useful examples of substituents which cause an increase of the amphiphilic nature of the compounds of formula (I) are: (1) long chain alcohols, e.g., -0 ^ 2 ^ 24-6) ^ wherein - ^ 12 ^ 24 J ^e hydrophobic (2) fatty acids and salts thereof, such as sodium oleic acid. (3) phosphoglycerides such as phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl choline, (4) sphingolipids such as sphingomyelin and (5) glycolipids such as glycosyldiacylglycerins, cerebrosides, sulfatesters of cerebrosides and gangliosides.

Preferably, X, Y, Z, X ', Y' and Z 'are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic acid ester, sulfonic acid or salt thereof, sulfonic acid ester , substituted or unsubstituted amino, cyano, nitro or biologically active, and Z 'is hydrogen or lower alkyl. In another embodiment, each of X, Y, X ', Y' is hydrogen and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid, carboxylic ester, sulfonic ester ( esters of aromatic sulfonic acid), nitro, amino (especially lower alkylamino), cyano and biologically active groups.

In another embodiment, X, Y, Z, X'and Y 'are selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR wherein R is an alkyl group or a fatty acid group of 6 to 18 carbon atoms , fluorine, chlorine, iodine, bromine, -C (O) -OCH 8, cyano, nitro or ligand specific for the biological receptor.

In another preferred embodiment, X, Y, X ', Y' and Z are selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid, carboxylic acid ester residue, sulfonic acid residue, sulfonic acid ester residue, nitro group , amino, cyano and biologically active groups.

In an even more preferred embodiment, at least one of X, Y, X ', Y' and Z is a biologically active group or substituent that enhances the amphiphilic nature of the molecule.

Particularly preferred specific examples of groups that may serve as one or more substituents up to are set forth in the following overview:

Υ X

γ · X ·

X X ' Υ Υ ' 2 -Η -Η -Η -Η -H -ΟΗ -Η -Η -Η -H -Η -Η -ΟΗ -Η -H -Η -Η -Η -Η -OH -Η -Η -ΟΗ -ΟΗ -OH -Η -Η -Η -Η -SO ₃ H (Na) -ch ₃ -CH ₃ -Η -Η -CN -Η -Η -OCH ₃ -OCH ₃ -och ₃ -Η -Η -Η -Η -COOH (Na) -Η -Η -COOH (Na) -COOH (Na) -H -Η -Η -Η -Η -C ₆ H ₁₂ COOH (Na) -Η -Η -Η -C ₆ H ₁₂ COOH (Na) -H -Η -Η “CgHi ₃ -Η -SO ₃ H (Na) -Η -Η -Η -COOH (Na) -tert-Butyl -Η -ch ₂ nh ₂ -Η -Η -H -Η -Η -Η -Η -nh ₂ -ΟΗ -Η -Η -Η -ch ₂ nh ₂ -Η -Η -Η -Η -c <h ₈ nh ₂ -Η -Η -Η -COOCH ₃ -COOH (Na) -ΟΗ -Η -Η -coonhch ₃ -H -Η -Η -Η -coonhch ₃ -COOH (Na) -Η -Η -Η -imidazoyl -H -Η -Η -Η -glycinyl -H -Η -Η -Η -steroidyl -H -Η -Η -Η -glycosyl -H -Η -Η -Η -H -imidazoyl -Η -Η -Η -Η -glycinyl -Η -Η -Η -H -steroidyl -Η -Η -Η -H -glycosyl

X X ’ Υ Υ ' - - - - J. - - - Ζ ' -Η -Η -Η -Η -Η -Η -Η -Η -Η -ch ₃ -Η -Η -Η -Η - c ₆ h ₁₂ oh -Η -Η -Η -ΟΗ -Η -Η -Η -ΟΗ -Η -Η -Η -Η -Η -COONHCHj -Η -Η -Η -Η -Η -benzyl -Η -Η -Η -C ₆ H ₁₂ OH -ch ₃ -Η -Η -c ₆ h ₁₃ -Η -ch ₃

Specific examples of such compounds are:

»-Coch

0 «

where

R = H, C8 to C18 or a fatty acid

wherein R is methyl, ethyl or propyl; and

Substituents

OH

Examples of cationic compounds are:

and anionic water-soluble

The process step and the process for the preparation of the compounds of the invention comprise the osmylation of the meso-substituted mataloporphyrin of formula (III), or the corresponding demethylated porphyrinogen of formula (IV), thereby forming an β, β'-position of the eightate ester. The starting meso-substituted metalloporphyrin (III) or porphyrin (IV) for this reaction can be prepared by one of the known methods. Examples include the following:

(1) Pyrrole is reacted with suitably substituted benzaldehydes by the Adler method, according to Adler et al. A Simplified Synthesis of Meso-Tetraphenylporphyrin

J. Org. Chem., 32, 476 (1967), or Lindsey, which is described in Investigation of Synthesis of Meso-Porphyrins Employing High Concentration Conditions and an Electron Transpatent Chain for Aerobic Oxidation, J. Org. Chem., 1994, 59, 579-587. For the preparation of the meso-tertraalkylated compound, simple reactions are described in Facile Syntheses of Tetraalkylorine and Tetralkylporphyrin Complexes and Comparison of the Structures of Tetramethylchlorine and Tetramethylporphyrin Complexes of Nickel (II), J. Am. Chem. Soc.,

102: 6852-54. (1980).

(2) Condensation of Dipyrrole Compounds and Corresponding Parts as described in Wallace et al., Rational Tetraphenylporphyrin Syntheses: Tetraarylporphyrin from MacDonald Route, J. Org. Chem., 58, pp. 5983-5993 (1993) (3) Manipulation of porphyrin in its J- or meso-poloyum, eg as described in Di Magno et al., Facile Elaboration of Porphyrins Via Metal Mediated Cross Coupling, J. Orq. Chem., 58, 5983-93 (1993) or Osuka et al.

Synthesis of 5,15-Diaryl-Substituted Oxochlorins from 5,15-Diaryl-Ethyl Porfyrin, Bull.Chem.Soc. Japan, 66, pp. 3837-3839 (1993), or by converting phenyl substituents to pre-existing and suitably substituted mesoporphyrins, described in Hombrecher et al., An Efficient Synthesis of Tetraaryl Porfyrins 12, pp. 2447-2456 (1993).

Everything that is contained and explained in the above-cited publications referred to herein is hereby incorporated by reference.

Preferably, the compound of formula (III), which is used as the starting material in step a, can be prepared by the method of Lindsey et al. for the synthesis of porphyrins (see above).

The reaction may be described as follows: and suitably substituted in a nitrogen atmosphere to oxidize the thus formed

In general, the procedure for carrying out these usually equimolar mixtures of benzaldehyde pyrrole can be reacted by the presence of an acidic porphyrinogen catalyst by air or by treatment with DDQ as an oxidizing agent to provide porphyrin which is then usually purified by column chromatography.

The osmylation reaction of step a is carried out by treating the starting material OsO ₄ in the presence of a base, usually pyridine, to form an δ, β'-position of the eightate ester as shown below:

Quantity 0s0 ₄ is generally stoichiometric, however, and generally ranges between about 1.0 to 1.5 moles per mole of starting material.

The principle, which is usually used along with 0s0 ₄ is generally one of those bases which have the ability to coordinate to the osmium (IV) in eight ester. In this way, the base stabilizes the intermediate and accelerates the formation of the ester of the osmiate. See, for example, Schroder, Osmium Tetroxide Cis Hydroxylation of Unsaturated Substrates, Chem. Rev., 80: 187-218 (1980). Preferred bases are pyridine, imidazole, isoquinoline, tert-alkylamines such as trimethylamine, methylsulfonamide and the like. The amount of alkali can vary greatly up to the full saturation of the coordination sphere of osmium (VI) in the eighth ester. Preferably, however, the amount of base used is in the range of about 2 to about 20 equivalents. Some bases, such as pyridine, may also play the role of solvents and co-solvents for the osmylation reaction.

Although it is possible to add to the reaction 0s0 ₄ itself, it is better to pre-dissolved in a suitable unreactive solvent. If a solvent is used, its choice depends on the nature of the entire set of substituents which contains the starting porphyrin, since these affect its solubility. However, a typical enumeration of envisaged solvents is included, including aromatic solvents such as pyridine, toluene and benzene, chlorinated solvents such as CHCl 3 and dichloromethane, water, ethers such as diethyl ether, tetrahydrofuran, diethylene glycol and glycol dimethyl ether (ethylene glycol dimethyl ether), ketones such as acetone and methyl ethyl ketone, acetonitrile, DME, DMF and DMSO, alcohols such as ethanol, methanol and butanol, and mixtures thereof.

If the starting material is water soluble, the preferred solvent is water. When an organic solvent is used, solvent systems that include combinations of chlorinated solvents such as CH 2 Cl 2 and dichloromethane in admixture with 2 to 25 volume% pyridine are particularly suitable.

The temperature of the reaction mixture during step a may vary widely and is typically maintained at room temperature, or more or less the reaction mixture is cooled to a temperature in the range of about -10 ° C to room temperature. Preferably, the reaction is carried out at about room temperature.

The time required to carry out the osmylation reaction of the step depends largely on the temperature to be used and the relative reactivity of the starting materials. Particularly, if the meso34 substituents are an aryl or bulky alkyl group such as tert-butyl, the progress of the reaction is relatively slower due to the spherical hindrance of the J-position against the attack of the bound OSO4 (VIII) in the form of OSO4 (complexed with a base such as pyridine). Therefore, di-meso-substituted systems also react relatively rapidly to tetra-substituted systems when they have one or more of their particular substituents up to a large volume, i.e., the substituent is a tert-butyl group, a cycloalkyl group or a substituted phenyl ring , it may take longer to fully react. As can be seen, the reaction time varies greatly, from 1 hour to 7 days.

The osmylation reaction can also be carried out at or above atmospheric pressure. Preferably, however, the pressure is approximately equal to atmospheric. The reaction may be carried out in the presence of a gas mixture of about air, but if too reactive reagents are used, the gas mixture may be enriched with an inert gas such as nitrogen, argon and the like.

The oshylation step according to the invention can be carried out under normal ambient light conditions. However, due to the nature of the starting and resulting compounds, photosensitizers are also suitable and light exclusion is generally advantageous to minimize side reactions.

The course of the reaction is sometimes accompanied by a change in the color of the reaction mixture, for example from purple to green. Other known methods, such as various types of chromatography, particularly TLC and HPLC, can be used to monitor the progress of the reaction to control the loss of starting materials.

At the conclusion of the osmylation reaction, the resulting reaction mixture is formed, from which the diol product is separated and purified in any known manner, usually by chromatography. Preferably, however, in the reduction step b, the osmylation reaction mixture is used directly without isolation or purification of the intermediate necessary for the second reaction present in the reaction mixture.

The reduction of the osmylation reaction mixture to prepare the diol of formula (I) can be accomplished by many reducing agents used. Examples of such reducing agents are gaseous H ₂ S, HSO 3 ^- , BH 4, AlH 4 -, B2 H 8, H 2 with a catalyst of Ni or Pd, Zn / H ⁺ and the like. Particularly suitable reducing agents are H ₂ S and HSO ₃ ", of which H ₂ S is more preferred.

Most of the abovementioned reducing agents are used in combination with suitable non-reactive organic or inorganic liquid substances in which the agent is not soluble (so-called non-solvent) such as methanol, ethanol and the like, the addition of which also increases the solubility of the dihydroxylated product. it has an anionic or cationic character. Sometimes it also helps to isolate and purify the product with a co-solvent. A particularly preferred combination of the reducing agent and the co-solvent for step b is H ₂ S with methanol.

Specific examples of reducing agents suitable for direct addition to the reaction mixture at the end of the oscillation step and, without isolation or purification of a particular compound that is present as an intermediate in the osmylation mixture include:

(1) action and methanol, and (2) vigorous stirring of the organic phase with a solution of HSO _g ^_ to In these cases the reaction may proceed at a rate sufficient to generally present at a first (1) of the process or can take place as dependent, which however has results in a significantly lower reaction rate as in the second (2) process. Thus, the rate of reaction is influenced by the nature of the reducing agent and at the same time by the presence or absence of a co-solvent, the purpose of which is to remove the unreacted portion of the reducing agent by converting it to the solid phase.

The temperature of the reaction mixture during reaction step b can be used over a very wide range, depending on which reducing agent is used. For example, when H2S gas is used as the reducing agent, the temperature is left at room temperature. However, for other reducing agents, the temperature may range from 0 to 100 ° C.

The time required for the reduction reaction in step b to a large extent depends on the temperature and the relative reactivities of the starting materials, but is preferably room temperature. The reduction step b can be carried out in the presence of gases at pressures above and below atmospheric pressure. However, it is most common to carry out the reaction at about atmospheric pressure.

The resulting product, which is a β, β'-dihydroxy mesosubstituted, chlorine, bacteriochlorine or isobacteriochlorine compound of formula (I) or formula (II), can be isolated by any known method, such as separation with a non-solvent reducing agent (nonsolvent). , precipitation, immiscible liquid extraction, solvent evaporation or a combination of these or other known methods. Usually, the β, β-dihydroxy compound of formula (I) or (II) can then be purified by one or more methods such as recrystallization, various forms of column chromatography, non-solvent or partially dissolving trituration, countercurrent extraction methods and the like.

The general procedure for performing a typical combination of osmylation and reduction reactions is given below:

A known amount of 5,10,15,20-meso-tetrafenylporphyrin is stirred in CHCl 3: pyridine 40: 1 and 1.3 equivalents of OsO 2 is added. The reaction mixture is then quenched by bubbling gaseous gas for several minutes. After addition of methanol, the black OsS precipitate is filtered off. The filtrate is evaporated to dryness, chromatographed using, for example, silica gel / CH 2 Cl 2 -5% methanol and further purified by recrystallization.

If the demetalization of the β, β'-dihydroxy compound of formula (II) is desired, it can be carried out in several stages during the process of the invention. Either (1) is based on a demetalized meso-substituted porphyrinogen compound of formula (IV), which is represented by the structural formula in the following figure:

or (2) meso-substituted meso-substituted metalloporphyrin and metal M is removed from the compounds by treating the reaction mixture from step aa before reduction step b, or (3) demetallizing a β, β'-dihydroxy meso-substituted compound of formula (I) after reduction step b to form a compound of formula (II).

The presence of the metal M is generally not necessary in carrying out the osmylation step a or the reduction step b, but in many cases its presence increases the solubility of the starting compounds so that a higher concentration of reagents can be worked and thus the reaction time is shortened. Therefore, it may be considered more advantageous for the metal to be present, especially in carrying out the ossification step and method of the invention. However, it should also be noted that in addition to the metal, many of the substituents on the meso-substituted compound can significantly affect solubility. Thus, even in this manner, the concentration can be increased and the reaction time reduced.

When demetlating the β, β'-dihydroxy compound of formula (I) or the corresponding compounds after the osmylation step or the corresponding compounds after the osmylation step b, the reaction conditions are usually identical or very similar. A suitable demetalate for this reaction is any acid that is capable of inducing demetalate but does not promote the formation of oxo-porphyrins. The choice of reaction conditions should take into account the presence of particular substituents on the demetallized compound.

It is usually not possible to use mineral acids such as sulfuric acid and hydrochloric acid, since these acids together with the demetalate cause rearrangement / dehydration of the basic diol to give the corresponding oxo-porphyrin. The demetlating agent is preferably selected from the group consisting of CH 3 COOH, CF 3 COOH, H ₂ S, 1,3-pandanediol, dilute hydrochloric acid, the diluent being, for example, water or chloroform, and mixtures thereof. Examples of a suitable mixture of demetallizing agents are (1) dilute trifluoroacetic acid, (2) H ₂ S and (3) a two-phase system consisting of chloroform and dilute (5%) hydrochloric acid.

Although demetalaction reactions are well known to those skilled in the art of organic synthesis, particularly those dealing with compounds of the same type to which the compounds of the invention belong, such that they can be performed using a conventional routine, further information about the reaction obtain by JVBuchler, Synthesis and Properties of Metalloporphyrins, The Porphyrins, Volume I, Chapter 10 (2978). The aforementioned demetallizing agents may also be advantageously used in combination with a suitable non-reactive solvent in some cases. Examples of useful or suitable solvents are water, alcohols such as ethanol, methanol, isopropanol and the like, haloalkanes such as methylene chloride and the like, nitrogen containing solvents such as DMF, tetrahydrofuran and the like, relatively unreactive aromatic compounds such as benzene, toluene and the like and ethers such as diethyl ether, diethylene glycol and glycol dimethyl ether.

The temperature of the reaction mixture during the disassembly may vary, but is usually maintained in the range of about 0 to 120 ° C. For example, refluxing acetic acid may be used as a demetlating agent, so that the reaction temperature will be about 118 ° C. However, in most cases and most preferably, dematallization is carried out at or below room temperature.

The time required to carry out the demetalate reaction varies within a very wide range, depending on the temperature used and the relative reactivities of the starting compounds, in particular the nature of the demetalate and the metal to be removed from the porphyrin. For example, if 5% aqueous hydrochloric acid and chloroform are used in the biphasic system reaction and the demetalized compound is a zinc porphyrin complex, the reaction will take a few minutes. However, when the rearrangement is performed, the metal compound can be subjected to more aggressive stronger acid conditions, such as treatment with dry hydrogen chloride in chloroform, whereby rearrangement, metal removal, or both can be achieved.

The reaction can be carried out above or under atmospheric pressure. Preferably, the reaction is carried out at a pressure about equal to atmospheric pressure.

Direct methods such as neutralization of the reaction mixture, immiscible liquid extraction, silica gel column chromatography or other types of chromatography, separation in a liquid in which undesirable substances do not dissolve, precipitation or crystallization, solvent evaporation or some combination may be used to isolate the demetalized product. of these or other known methods. Preferred methods for isolating the compound produced include chromatography and / or crystallization. If further purification of the demetalized product is desired, it may be subjected to additional purification procedures such as recrystallization, silica gel column elution, and combinations of these methods.

Due to the mechanism of oxidation of olefins OSO ₄ , the resulting β, β'-dihydroxy compounds are obtained in step a and step b of vicinal diols. The introduction of vic-diol gives the compound an amphiphilic character, a desirable property that is important in the biodistribution of site-specific photochemotherapeutics. In addition, the conversion of porphyrin to chlorine alters the optical properties as desired (tetrafenylporphyrin has: S _max [benzene] = 653 nm and log M = 3.80 while 2,3-vic-dihydroxytetrafenylporphyrin has S _max [CH 2 Cl 20.1% MeOH] = 644 nm and log M - 4.38). By converting dihydroxychlorine to tetrahydroxybacteriochlorine, this effect is even more pronounced (2,3,12,13tetrahydroxybacteriochlorine (S _max [CH 2 Cl 2 0.1% MeOH] - 708 nm and log M = 4.89). This increase in log M and S _max means that Chlorine absorbs light about 4.0 times more in the red region of the spectrum than the starting porphyrin, a result of Q-bond enhancement.

It should further be noted that the compounds of the invention are surprisingly stable against dehydration and undesirable reconstitution of the porphyrin chromophore. For example, it has now been found that a solution of HCl in CHCl 3 under reflux conditions can be successfully used to demetalate the chlorine of formula (I) wherein M is Zn without causing undesired rearrangement reactions. To achieve the expected dehydration and rearrangement to the corresponding oxo compound, a catalytic amount of HCIO4 should be added.

Dissolved HCl CHCl 3 reflux

In the same way as, as mentioned above, meso-tetrafenylchlorine is treated with a stoichiometric amount of OSO4 followed by reduction of the intermediate, 2,3-more-dihydroxy-meso-tetrafenyl-bacterichlorine is obtained.

However, the introduction of Zn (II) as a metal ion into the chlorine results in a change of the resulting compound, instead of (2,3-vic-dihydrxyisobacteriochlorinato) Zn ²⁺ , which can be demetallized under mildly acidic conditions to give 2,3-vicdihydroxyisobacteriochlorine. This reaction sequence is shown in the scheme below to show the central metal control influence, if present.

racemic.4; M = Zn racemic. M = 2H

HCl

The cause of this phenomenon is not fully explained. Some authors suggest such an explanation that the reduced double bond present in the chlorine compound allows a path for the delocalization of X-electrons that are isolated and symmetrically positioned opposite the pyrrole double bond. This attack is considered to be stronger than the double bond attack in the adjacent pyrrole core and causes minimal loss of X-energy, leading to the selective formation of the bacteriochlorin compound. The introduction of a metal (or proton) may cause a change in the preferred X-location of the isolated double bond on the adjacent pyrrole core, resulting in the formation of metalloisobacteriochlorine.

The β, β'-dihydroxy meso-substituted chlorinated, bacteriochlorinated and isobacteriochlorinated compounds of the invention can also be subjected to reaction steps a and b again to add a second pair of hydroxy groups to the molecule. The relative position to which the other two hydroxy groups are bound will depend on many factors, such as the presence of the metal, the choice of metal if present, the relative bulkiness and electrical properties of the meso-substituents, and the presence and optionally the properties of the other β, β´-substituents.

Of particular interest, as in the previous cases, is the importance of the metal M to influence the sites of attachment of the second pair of hydroxy groups to the preferred positions. For example, when the demetalized diol chlorine of formula (II) is oshylated by the method of the invention, the second pair of hydroxy groups is bonded to the β, β'-position on the opposite ring. Conversely, if the metallized compound is a compound of formula (I), for example one in which M is zinc, the second pair binds to the β, β'-position on the adjacent ring. This phenomenon has also been observed analogously in other reactions, for example in the diimide reduction of porphyrins described by Vhitlock et al., Diimido Reduction of Porfyrins, in J, Am. Chem. Soc., 91, pp. 7485-7489 (1969), upon oxidation oktaalkyl ehlorinů 0s0 ₄ described in the publication by J. Chang et Chem. Soc., Chem. Commun., Pp. 1213-al. in the journal 1215 (1986), in the catalytic reduction of pheophorbides

Ni ¹¹ na

Raney nickel as described in Smith et al.

in J. Am. Chem. Soc., 107, pp. 4954-4955 (1985) and in the OsO ₄ phosphocorbide osmosis, described in the authors publication.

Pandey et al. in Tetrahedron Letters. 33. p. 7815 to p

7818 (1992).

If β, β'-dihydroxylation in a 1: 1 molar ratio is a mixture of two (vic-dihdroxy) bacteriochlorines, as follows:

diol chlorine, the 2,3,12,13-bis isomers shown in the figure

An isomer bearing all the hydroxyl side of the plane of the porphyrin structure can be isomers due to the fact that there is a difference in polarity between the groups on one another by their molecules and therefore the separation can be performed by column chromatography. An isomer with all hydroxy groups on one side has a stronger amphiphilic character as the polarity of the molecule is oriented to one side. The absorption characteristics of hydroxybacteriochlorines are in the preferred range for use as photosensitizers in photodynamic therapy.

When β, β'-dihydroxylated with a zinc metal diol chlorine, it is formed in a 1: 3 molar ratio of metalloisobacteriochlorines (shown below as shown in the figure below):

1. 0s0 ₄

2. H ₂ S

Although this is not fully explained at present, it is believed that steric hindrances cause this deviation from the ratio of isomers in the 1: 1 reaction mixture formed. The compound below (C 6 placement) appears as a racemic mixture, while the compound of the above formula (C placement groups) is not chiral.

The β, β-dihydroxy-substituted-chlorines, bacteriochlorines or isobacteriochlorines of the invention can also be dehydrated using acid hydrolysis to give the corresponding 2-oxy- (meso-tetrafenyl) porphyrins, which can serve as a starting material for a novel synthetic route of this type of compounds. Although few of these compounds are accessible by other syntheses, e.g. Catalano et al. Efficient Synthesis of 2-Oxy-5,10,15,20-tetrafenylporphyrins by Novel Multistep China-substitution Sequence, J. Chem. Soc., Chem. Comm., Pp. 1537-1538 (1984), many other compounds can be prepared by the dihydroxylation method of the invention. Specific examples of such compounds are provided below:

(A) 2-oxy-12,13-dihydro-meso-tetrafenylporphyrin, (B) 2-oxy-7,8-dihydro-meso-tetrafenylporphyrin and (C) 2,12-dioxy-meso-tetrafenylporphyrin.

Other synthetic routes of potential interest are the formation of isopropylidene ketal, which may be useful in fine-tuning the solubilities, biodistribution properties and amphiphilites of the compounds of the invention even without compromising the quality of the spectral values.

The β, β'-dihydroxy meso-substituted chlorines, bacteriochlorines or isobacteriochlorines of the invention are useful as photosensitizers and may therefore be used in photodynamic therapy (PDT) and may further serve as intermediates for the production of other photosensitizers. Specifically, they are photosensitizers that are used to increase the sensitivity of neoplastic cells or other abnormal tissues to achieve destruction by visible light. In photoactivation, according to theoretical ideas, photoactivation energy is transferred to endogenous oxygen, converting it to atomic oxygen. This atomic oxygen, as reported, is responsible for the observed cytotoxic effect. Alternatively, direct electron transfer from a photoactivated molecule may occur. The method of van Lier, Photobiological Techniques, 216, pp. 85-98 (Valenzo et al. Editors 1991) recognizes the ability of each particular compound to generate atomic oxygen on an effective scale, making it a good candidate for use in photodynamic therapy. Furthermore, it should be added that photoactivated forms of porphyrin are able to fluoresce and this fluorescence may aid in tumor imaging.

Typical indications known for these compounds in the art include diagnosis and destruction of tumor tissue in solid tumors such as bronchial, cervical, esophageal, and intestinal cancer, plaque dissolution in blood vessels (see, e.g., U.S. Patent No. 4,512,672, which hereby incorporated by reference), treatment of superficial diseases such as acne, athletic foot, warts, papilloma and psoriasis, and treatment of biological products such as blood for transfusion to prevent infection.

Further, when metals such as In or Tc are used, the metallized compounds of the invention have utility in nuclear diagnostics. Similarly, when M is Mn (III) or Gd (III), the compounds may be useful after magnetic resonance imaging. In these applications, the use of the compounds of the invention can also achieve a significant improvement in biodistribution due to the variability due to the change of substituents on the backbone.

The photosensitizers produced from the compounds of the invention may further be formulated into pharmaceutical compositions for administration to a living subject, or administered in vitro using techniques well known in the art. A summary of such pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. The compounds of the invention may be used alone or as components of mixtures.

In general, for the diagnosis or treatment of solid tumors, a compound of the invention, labeled or unlabeled, is administered systemically, such as by injection. The injection may be intravenous, subcutaneous, intramuscular or even intraperitoneal. For injection, the usual forms of liquid solutions or suspensions, solid forms suitable for reconstitution into a solution or suspension for injection or emulsion, are used. Suitable additives are, for example, water, brine, dextrose, glycerin and the like. Of course, these compositions may also contain small amounts of non-toxic auxiliary ingredients such as wetting agents, emulsifiers, pH buffers, and the like.

Systemic administration can be accomplished by implantation of a slow or sustained release system, suppository, or in a suitable formulation, orally. The composition and preparation of these formulations are generally known in the art, and a summary thereof can be found in Remington's Pharmaceutical Sciences (supra), cited above.

If the action of the compounds is to be local, such as in the treatment of superficial tumors or skin diseases, the compound may be applied by application in a suitable composition such as a lotion, suspension or paste.

The amount of photosensitizer administered depends on the choice of the active ingredient, the conditions, the route of administration, the individual characteristics of the subject and the judgment based on practical experience. Depending on the specific characteristics of the preparation, smaller or larger doses are used. For compositions that are highly specific to target tissues, such as a highly specific monoclonal immunoglobulin preparation or a specific receptor ligand, dosages in the range of 0.05 to 1 mg / kg are recommended. For compositions that are less specific to target tissues, larger doses of up to 1 to 10 mg / kg may be required. These ranges are only recommended because in many individual cases the need for a dose well in excess of these recommended limits cannot be excluded.

In addition to in vivo use, the compounds prepared from the intermediates of the invention can be used by treating certain substrates in vitro to destroy dangerous viruses or other infectious germs. For example, blood plasma or blood for transfusion or storage in blood banks for future use for transfusion may be treated by the addition of the invention and sterilized by irradiation. Further, the compounds of the present invention can be irradiated in the presence of the compounds of the invention by biological products obtained from biological fluids such as Factor VIII, thereby destroying contaminants therein.

Further, since the moieties up to the meso positions may be identical or different, or substituted further symmetrically or asymmetrically, the compounds of the invention may be finely tuned to obtain the desired combination of biological effects when administered to a subject for photodynamic therapy. A specific example of fine tuning of the solubility, biodistribution and / or amphiphilic nature of the compounds of the invention is the preparation of the corresponding isopropylidene ketal. In addition, the invention provides methods for synthesizing such compound derivatives in an effective form and with relatively small amounts of by-products or isomeric undesirable impurities.

The invention will be further elucidated by the following examples, which are intended to be purely illustrative and not limiting of the scope of the invention:

Example 1: β, β'-dihydroxylation to prepare tetrafenylchlorine tetrafenylporphyrin for 3,4-dihydroxy-5,10,15,20-

1.00 g (1.63 x 10 -3 moles) of 5,10,15,20-meso-tetrafenylporphyrin were stirred in 200 ml of freshly distilled ethanol-stabilized CHCl 3. 5.0 ml of freshly distilled pyridine and 540 mg (2.12 x 10 mol, 1.3 equivalents) of OsO 2 were then added to the obtained mixture. The reaction flask was sealed and stirred at room temperature in the dark for four days. The reaction was quenched with H 2 S gas purification for five minutes. After addition of 20 ml of ethanol, a black OsS precipitate was filtered on a diatomaceous earth filter (commercially available under the name Cellit). The resulting filtrate was then evaporated to dryness and the residue was loaded onto a silica gel column (200 g, 280-400 mesh) eluting with 1,1-dichloromethane to remove unreacted starting materials (400 mg, 40%). from a column of 1.5% 8.02 x 10 ^-4 mol, in dichloromethane of bacteriochlorines

The produced β, β'-dihydrochlorin was then eluted with ethanol in 1,1-dichloromethane (520 mg,

49% yield). Finally, crude tetrahydroxy (40 mg, 3.5%) was eluted with 5.0% methanol. The produced β, β'-dihydroxychlorine was recrystallized from CHCl 3 / methanol and then had a melting point above 350 ° C. The UV to vis spectrum of the β, β'-dihydroxychlorin thus obtained was typical of chlorines and is shown in Figure 1.

_Rf. = 0.68 (silica gel, CH ₂ C1 ₂ / 1.5% methanol) ^{Χ Η} NMR (400 MHz, CDCl ₃₎ L = -1.78 (br s, 2H, NH), 3.14 (with,

2H, OH, exchangeable with D ₂ 0), 6.36 (s, 2H, pyrrolidine-H), 7.68-7.80 (m, 12H, phenyl- (m, p) -H,

7.92 (d, J = 8.5 Hz, 2H, phenyl-H), 8.09 (br s, 4H,

o-phenyl-H), 8.15 (d, J = 8.5 Hz, 2H, o-phenyl, 8.33) (d, J = 7.9Hz, 2H, J ' -H), 8.48 (s, 2H, J-H), 8.63 (d, J = 7.9 Hz, 2H, J-H), ¹³ H NMR (125 MHz, CDC1 ₃₎ L = 73.9 113, 2 123.1 124.2 126.7 127, 5,127.7 127.9 128.1 132.2 132.7 133,9 134, 1 135.5 140.6 141.2 141.8 153.2 161.4 UV-Vis (ch ₂ or ₂ .o, i % MeOH): S (nm) (log M) 408 (5.27), 518 (4.19), 544 (4.19), 592 (3.85), 644 (4.38),

Fluorescence at 649 nm (excitation wavelength at 408 nm, 1.10 x 10 ^-6 M in CH ₂ Cl ₂ ),

LR-MS (EI, 300 ° C) m / e (%): 648 (0.5, M ^& lt ^{; +} & gt ^; ), 646 (0.9, M ⁺ -2H),

630 (100, M ⁺ -H ₂ O), 614 (42.7),

HR-MS (EI, 250 ° C): calculated for C ₄₄ H ₃₂ N ₄ O ₂ : ... 648.2525 found: ................... 648 , 2525

For C ₄₄ H ₃₂ N ₄ O ₂ 1 / 2H ₂ O: C: 80.34 H: 5.08 N: 8.52 found: ............... C, 80.26; H, 4.93; N, 8.46

Example 2:

β, β´-Dihydroxylation of thiophenylporphyrin for the preparation of 3,4-dihydroxy-5,10,15,20-tetrafenylchlorinato zinc (II):

The preparation of the zinc metal compound analogous to the compound of Example 1 above is based on the substrate of Example 1, which is only adapted to the higher solubility of the starting metallated compound, which is 5,10,15,20-mesotetrafenylchlorinato zinc (I). 520 mg of the starting compound was dissolved in distilled ethanol stabilized (7.37 x 10 ^-4 mol) 20 ml freshly

5.0 mL of freshly distilled pyridine and 225 mg (8.84 x 10 ^-4 mol, 1.2 equivalents) of OsO _{4 were} added to CHCl ₃ . The reaction flask was sealed and stirred at room temperature in the dark for four days. The reaction was quenched with H ₂ S gas purification for five minutes. After addition of 3 ml of methanol, a black OsS precipitate was filtered on a diatomaceous earth filter (commercially available under the name Cellit). The filtrate was evaporated to dryness and the residue was loaded onto a silica gel column (100 g, 280-400 mesh) eluting with 1,1-dichloromethane to remove unreacted starting material (55 mg, 11%). Manufactured β, β'-dihydroxymetalochlorinový product (380 mg, 5.34 χ ^10-4 mol, 72% yield) was then with 0.5% methanol in dichloromethane. The produced β, β'-dihydroxymetalochlorine was recrystallized from CHCl 3 / methanol and then had a melting point above 350 ° C. The UV-vis spectrum of the β, β'-dihydroxymetalochlorine thus obtained was typical of the metalochlorines and is shown in Figure 1.

Rj? = 0.62 (silica gel, QH-Clg / 1.5% methanol),

1 H NMR (300 MHz, CDCl 3) δ = 5.30 (s, 2H, OH, exchangeable with D 2 O), 6.12 (s, 2H, pyrrolidine-H), 7.55-7.72 (m, 12H, phenyl-H), 7.81 (dd, J = 1.4, 7.5Hz, 2H, phenyl-H),

8.37 (s, 2H, J-H), 8.48 (d, J = 4 Hz 2H, J-H) ¹³ H NMR (75 MHz, CDCl 3) L = = 50.633 126,482 126,585 126,629 127,226 127,351 127,479 127,684 127,766 127.815 129,307 132,114 132,523 133,628 133,680 133,789 141,729 142,573 146,516 148.038 154,217 156,279 UV-Vis (ch ₂ or ₂ . 0.1% MeOH) : S (nm) (log M) 418 (5.41)

614 (4.71),

Fluorescence at 620 nm (excitation wavelength at 418 nm, 1.18 χ 10 ' ⁶ M in CH ₂ Cl ₂ ),

LR-MS (+ FAB, 3-NBA) m / e (%): 710 (29.2, M ^& lt ^{; +} & gt ^; ),

693 (7.0, M ⁺ -OH), 676 (3.7, M + -2OH),

HR-MS (+ FAB, 3-NBA): calculated for 044Η3θΝ40 ₂ Ζη: 710,16602 found: .................. .710,16595

For C44H32N4O2. ^ / ₂ H2O.I / 2 C5H5N:

calculated .................... C: 73.42 H: 4.44 N: 8.29 found: ............ C: 73.50 H: 4.25 N: 7.87

Example 3: Synthesis of water-soluble chlorine 2,3-Dihydroxy-5,10,15,20-tetra- (4-pyridyl) zinc chlorinate (II)

The resulting compound of Example 3 was prepared analogously to the general procedure of Example 2:

_Rf. = 0.12 (silica gel, CH ₂ Cl ₂ / 10.0% MeOH / 2.0% pyridine);

_{UV-Vis? Max} = 408 (sh), 424 (Soret), 526, 570, 598 629 nm, MS (+ FAB, thioglycerine) m / e (%): 715 (56, M ^+);

697 (27, M ⁺ H ₂ O)

HR-MS (+ FAB, thioglycerine):

calculated for 0 ₄ θΗ ₂ ^ Νβθ.2Zn: ............ 714.14702 found: ...................... ......... 710.15401

Example 4: Preparation of cis-2,3-dihydroxytetrafenylbacteriochlorine

The above compound was prepared according to the general procedure of Example 1. Thus, tetrafenylporphyrin was first oxidized with 1.22 equivalents of OsO ₄ for two days. The oxidation reaction was stopped with 1S and the product was purified by chromatography. Yield: 53%

= 0.78 (silica gel, CH 2 Cl 2 / 2.5% methanol), ¹ H NMR (400 MHz, CDCl ₃ ) L = -1.58 (s, 2H, NH), 3.00 (s,

2H, OH,), 3.94-4.21 2H, (m, 4H, pyrrole 2, 3H), 6.13 (s, 2H pyrroline-12, 13-H), 7.58-7.73 ( m, 12H, phenyl ^{A, B-} (m, p) -H, 7.79 (br tr, J = 6.8 Hz, 4H, phenyl ^A- oH), 7.86 (br, d, J = 4) 4 Hz, 2H, phenyl ^B -oH), 7.97 (dd, J = 4.8 2Hz, 2H, phenyl ^B -o'-Η), 8.13 (2 overlapping second signal), 4H, (J J, -H),

UV-Vis (CH ₂ Cl ₂ · 0.5% MeOH): S (nm) (log M) 378 (4.96),

524 (4.49), 724 (4.71),

LR-MS (+ FAB, 3-NBA) m / e (%): 650 (100, M ^& lt ^{; +} & gt ^; ),

633 (19.2 M ^{+ -} OH),

HR-MS (+ FAB, 3-NBA): calculated for C ₄₄ H ₃₄ N ₄ O2: 650.26818 found: ................. 650.27118

Example 5: Preparation of two isomeric tetrahydroxytetrafenylbacteriochlorines: 2R, 3S, 12R, 13S-tetrahydroxy-5,10,15,20tetrafenylbacteriochlorine and

2R, 3S, 12S, 13R-Tetrahydroxy-5,10,15,20tetrafenylbacteriochlorin

100 mg of the starting compound mentioned above (1.54 x 10 -4) were dissolved in a minimum amount of CHCl 3 containing 10% pyridine (ca. 4 ml). To this was added 51 mg of OsO ₄ (1.3 equivalents) and the sealed solution was stirred at room temperature until the 644 nm chlorine peak was largely replaced by a 708 nm bacteriochlorin peak (16 hours). The oxidation reaction was then quenched by bubbling hydrogen sulfide gas (1S) through the reaction mixture. After filtering the solution to separate the precipitate and solvent, it was evaporated from the filtrate by evaporation. The resulting mixture was partitioned on a TLC plate (silica gel, 2 mm, 5% MeOH in CH 2 Cl 2 as eluent, double pass through a chromatography column). The off-white starting compound eluted faster, with almost the first fraction of eluent, while the dark pink bacteriochlorins followed at the following elution fractions:

E-isomer: Rf (silica gel, 5% MeOH in CH2Cl2) = 0.51

Z-isomer: R f (silica gel, 5% MeOH in CH 2 Cl 2) = 0.30 After isolation and recrystallization in Q H 4 C 4 / hexane, the overall yield was 40%. The two isomers were obtained in a ratio of 1: 1 (21 mg each).

Since the symmetrical groups of the two isomers C2y and ¢2 ^ are not distinguishable by NMR, UV-Vis or MS, they were assigned non-binding E- and Z- configurations to individual bacteriochlorines based on their chromatographic behavior. It is assumed that a compound with both pairs of hydroxy groups on the same side of the plane of the porphyrin structure (Z-isomer) has a more polar character than those in which the pairs of hydroxy groups have an arrangement on opposite sides (E-isomer).

E-isomer:

R f = 0.51 (silica gel, CH 2 Cl 2 / 5.0% methanol), ¹ H NMR (300 MHz, DMSO-d 6): L = -1.65 (s, 2H, NH), 4.99 (d, J) = 4.9Hz, 4H, OH), 5.87 (d, J = 4.9Hz 4H, pyrrolidine-H), 7.6 (br m, 12H, phenyl m-, pH), 7.86 (br ( s), 4H, JH), 7.96 (d, J = 1.8Hz, 8H, phenyl-1H), ¹³ H NMR (75 MHz, DMSO-d6): L = 73.112 115.631 122.879

127,100 131.537 133.852 136.223 141.217

160.067

UV-Vis (CH ₂ Cl ₂ .0.5% MeOH): λ (nm) (log M) 376 (5.42),

528 (5.08) 708 (4.89)

LR-MS (+ FAB, 3-NBA) m / e (%): 682 (100, M ^& lt ^{; +} & gt ^; ), 655 (31.1, M ⁺ -OH), 648 (5.8, M ⁺ -2OH), 613 (6.4 M ^{+ -} 4 OH -),

HR-MS (+ FAB, 3-NBA): calcd for C ₄₄ H ₃₄ N ₄ O ₄ : 682.258 ??, found: ................... 682, 25470

Z-isomer:

= 0.30 (silica gel, CH ₂ C1 _2/5, O% methanol) ¹ H NMR (400 MHz, DMSO-d₆): L = -1.75 (s, 2H, NH), 5.05 (br s 4H, OH) 5.95 (s, 4H, pyrrolinin-H), 7.65 (br s, 12H, phenyl-p, -mH), 7.93 (br s, 4H, JH),

8.09 (s, 8H, phenyl-o-H),

UV-Vis (CH ₂ C1 ₂ .O, 5% MeOH): S (nm) (log M) 376 (5.42)

528 (5.08) 708 (4.89)

LR-MS (+ FAB, 3-NBA) m / e (%): 682 (19.4, M ^& lt ^{; +} & gt ^; ), 665 (7.4, M ^& lt ^{; +} & gt ^; -OH), 649 (9.4), 648 (7). 5 M ⁺ -2OH), 613 (1.5, M ⁺⁾

-4OH -Η),

HR-MS (+ FAB, 3-NBA): calcd for C ₄₄ H ₃₄ N ₄ O ₄ : 682.25797, found: ................... 682, 25518

Example 6

Pinacol rearrangement in which tetrafenylporphyrin (Compound No.

prepares J 3) and J-oxo0X0-

Compound 3: 2, oxy-5,10,15,20-tetrafenylporphyrin: Cp.3

100 mg (1.54 x 10 µmol) of the starting compound which is

3,4-dihydroxy-5,10,15,20-tetrafenylchlorine (Cpd.2), was dissolved in 10 mL of CH 2 Cl 2 and 3 drops of 70% aqueous HCl 10 solution were added to this solution. The mixture was refluxed for 3 minutes. The completion of the reaction was confirmed by the presence of a sharp peak of 520 nm in the UV-Vis spectrum of the sample that was collected and neutralized with Et 2 N for 3 minutes before the spectral values were measured. The resulting transparent green mixture was cooled, shaken with aqueous NH 4, dried over anhydrous Na ₂ SO ₄ , evaporated to dryness and chromatographed on silica (10 g, 280-400 mesh) with CH 2 Cl 2 eluent. The product, compound 3, was crystallized from CH 2 Cl 2 / hexane. Yield: 92 mg (95%).

Alternatively, zinc chloride was used as the starting compound. Under dehydration conditions (refluxing CHCl 3 with a drop of concentrated HCIO 4) the obtained product was demetallized to give compound 3. Complex compound 2, less labile in an acidic environment such as Ni-2 or with divalent Cu-2, was dehydrated under the same demetallings. Under more aggressive conditions, a drop of concentrated HCl under ambient conditions without disturbing (CHCl3 containing concentrated temperature), Zn-2 was demetallized without degradation

Zn-3: [2-oxy-5,10,15,20-tetrafenylporphyrinato] zinc

Compound 3 was metallized with Zn (II) acetate in pyridine / CHCl 3 to prepare Zn-3, identical to the compound described in Crossley et al. J. Org. Chem., 53: 1132-37 (1988).

Example 7: Isopropylidene acetal:

mg of [2,3-vic-dihydroxy-tetrafenylporfyrinatuo] zinc (11) was refluxed for 20 minutes in 10 ml of dry acetone with 100 mg of freshly dried ZnCl _second Evaporation to dryness and column chromatography (silica gel / CH ₂ Cl ₂₎ afforded 12.5 mg (60%) [2,3-di-0-isopropylidene) -5,10,15,20-tetrafenylchlorinato] zinc (II) .

¹ H NMR (300 MHz, CDCl ₃ ) δ = 0.61 (s, 3H, CH ₃ -a), 1.37 (s,

3H, CH ₃ -b), 6.46 (s, 2H pyrroline-H), 7.55-7.76 (m,

12H, phenyl ^{A, B-} (m, p) -Η), 8.05 (dd, 2.4 Η *, phenyl-o), 8.12 (hidden m, 4H, phenyl-o), 8.16 (d, J = 6.0 Hz, 4H, J H), 8.41 (s, 2H, J H), 8.53 (d, J = 6.0 Hz, 2H, J 1 -Η),

UV-Vis (CH ₂ Cl ₂ ): S = 418 (Soret), 520, 564, 594 (sh),

612 nm,

LR-MS (+ FAB, 3-NBA) m / e (%): 750 (11, M ^& lt ^{; +} & gt ^; ), 693 (23, M ⁺ C3 H60),

HR-MS (+ FAB, 3-NBA) m / e calcd for C 24 H 25 N 4 O 4 750.19732 found: ................. 750.19422.

Claims (51)

PATENT Claims β, β´-dihydroxy-meso-substituted bacteriochlorin or formula (I) or (II): an isobacteriochlorine chlorine compound is a metal selected from the group of Cu (II), Zn, Sn, Ge, Si, Mn (III), Gd (III, In and Tc) is a ring having the structure: which consists of Ni (II), Ga, Al, And which has the structure: D is a ring to R8 are independently hydrogen, a lower alkyl group, a lower alkylcarboxylic acid, an esterified acid group, a keto, hydroxy, nitro, amino, or a group which, linked to another ring, ring substituent or meso-substituent, forms a linked A 5- or 6-membered ring a S 1 to H are substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, which may be the same or different, provided that at least one general symbol through is not H. A compound according to claim 1 of formula (I), wherein M is Zn. A compound according to claim 1 of formula (II). A compound according to claim 1, the symbols A and D being a ring having the structure: wherein at least one of The compound of claim 1, wherein independently hydrogen, methyl, ethyl or lower to R 8 are alkyl esters. The compound of claim 1, wherein S ⁴ to S ⁴ are selected from the group consisting of phenyl, pyridinyl, N- (lower alkyl) pyridinium salts or naphthyl. A compound according to claim S ⁴ to S ⁴ having the structure 1, wherein at least one of Χ, Χ ', Y, Y' and Z is independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic ester, sulfonic acid or salt thereof, sulfonic ester an acid, substituted or unsubstituted amino, cyano, nitro or biologically active group, and Z 'is hydrogen or lower alkyl. The compound of claim 7, wherein each of X, Y, X ', Y' and Z is selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR wherein R is an alkyl group or a fatty group 6 to 18 carbon atoms, fluorine, chlorine, iodine, bromine, -Ο (Ο) -ΟΟΗβ, cyano, nitro or ligand specific for the biological receptor. The compound of claim 7, wherein X, Y, X ', Y' are all hydrogen atoms and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid, carboxylic acid ester residue. , a sulfonic acid residue, a sulfonic acid ester residue, a nitro group, an amino group, a cyano group, and a biologically active group. The compound of claim 7, wherein at least one of X, Y, X ', Y', and Z is a biologically active group or substituent that enhances the amphiphilic nature of the molecule. The compound of claim 1, wherein each of the S 1 to S 4 substituents is selected from the group consisting of phenyl, pyridinyl and N- (lower alkyl) pyridinium salts. The compound of claim 11, wherein S 1 to S 2 are identical to each other. 13. A process for the synthesis of a β, β-dihydroxy-meso-substituted chlorine bacteriochlorine or isobacteriochlorine compound of formula (I): where: is a metal Cu (II), Mn (III), is a ring selected from Zn, Gd (III, In and Tc) having the structure: which consists of Sn, Ge, Si, Ni (II), Ga, Al, D is a ring having the structure: to R 8 are independently hydrogen, a lower alkyl group, a lower alkyl carboxylic acid, an esterified acid group, a keto, hydroxy, nitro, amino, or a group associated with another ring, ring substituent or meso substituent to form a linked 5- or 6-membered circle a S ¹ to S 6 are H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, which may be the same or different, provided that at least one general symbol up to does not represent H, characterized in that it includes degrees: a. osmylation of the mesosubstituted metalloporphyrin of formula (III): where A, D, Rj to Rg, and S1S '^ are listed above to form the eighty ester in the β, β'-position and b. oxidizing said ester eightate to give the corresponding β, β-dihydroxy meso-substituted chlorine or bacteriochlorin of formula (I). 14. The process of claim 13 wherein M is Zn. 15. A method according to claim 13, wherein at least one of residues A and D has the structure: 16. The method according to claim 13, characterized in that at least one of the radicals R to R @ ₄ are independently hydrogen, methyl, ethyl, or lower alkyl. 17. The method of claim 13, wherein at least one of the residues up to has a structure: wherein X, Υ, X ', Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic ester, sulfonic acid or salt thereof, sulfonic acid ester, substituted or unsubstituted amino , cyano, nitro or biologically active, and Z 'is hydrogen or lower alkyl. The method of claim 17, wherein X, Υ, X Y, Y a and Z znamen are a biologically active or amphiphilic enhancing moiety. The method of claim 13, wherein said osmylating step a comprises treating at least one equivalent of SO ₄ with a meso-substituted metalloporphyrin of formula (III) in the presence of a base. 20. The process of claim 13, wherein in said osmylation step, a meso-substituted metalloporphyrin of formula (III) is reacted with OsO2 for from about 10 hours to about 5 days. The method of claim 13, wherein said osmylation step a) is carried out at room temperature and in the dark. 22. The method according to claim 13, characterized in that in said reducing step comprises treating said osmate ester with a reducing agent selected from the group consisting of H ₂ and ^H 2 SOg ^S · 23. Method for the synthesis of β, β'-dihydroxy-meso-substituted chlorine, bacteriochlorine or isobacteriochlorine of formula (II): where A is a circle that has the structure: R 8 to R 8 are independently hydrogen, lower alkyl, lower alkylcarboxylic acid. an esterified acidic group, keto, hydroxy, nitro, amino, or group linked to another ring, ring substituent or meso substituent, forms a linked 5- or 6-membered ring and, until they are H, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl substituted or unsubstituted aromatic rings which may be the same or different, with the proviso that at least one general symbol up to does not represent H, characterized in that it comprises the steps of: a. osmylation of a meso-substituted metalloporphyrin of formula (III) wherein M is a metal selected from the group consisting of Ni (II), Cu (II), Zn, Sn, Ge, Si, Ga, Al, Mn (III) , Gd (III, In and Tc) to form the eighth ester in the β, β'-position, b. a reduction of the ester eightylate in which the ester eightylate is converted to the corresponding β, β'-dihydroxy mesosubstituted chlorine or bacteriochlorin of formula (I); and c. demetalizing the β, β'-dihydroxy meso-substituted chlorine, bacteriochlorine or isobacteriochlorine of formula (I) from the reduction step to form the demethylated β, β'-dihydroxy meso-substituted chlorine of formula (II). 24. The method of claim 23 wherein M is Zn. 25. The method of claim 23, wherein at least one of the symbols A denoting and D is a ring having the structure: t i or 26. The process of claim 23 wherein up to R8 is independently lower alkyl esters. and hydrogen, methyl, ethyl A method according to claim 23, characterized in that at least one of the residues S ⁴ to S ⁴ has the structure: wherein X, Y, X ', Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic ester, sulfonic acid or salt thereof, sulfonic acid ester, substituted or unsubstituted amino , cyano, nitro or biologically active, and Z 'is hydrogen or lower alkyl. 28. The method of claim 27, wherein X, Y, Z, Y &apos; and Z are a biologically active or amphiphilic enhancing moiety. A method according to claim 23, wherein said osmylation step a comprises treating at least one equivalent of a 0so ₄ meso-substituted metalloporphyrin of formula (III) in the presence of a base. 30. The method according to claim 23, characterized in that in said step osmylačním reacting meso-substituted metalloporphyrin of formula (III) with OsO ₄ for a time from about 10 hours to about 5 days. 31. The method of claim 23, wherein said osmylation step a is carried out at room temperature and in the dark. 32. The method of claim 23, wherein t is in that in said reducing step comprises treating said osmate ester with a reducing agent selected from the group consisting of H ₂ and H ₂ SOg S. 33. The method according to claim 23, characterized in that in said step for demetalačním meso substituonvaný metalloporphyrin of formula (I) acts demetalačním agent selected from the group consisting CHgCOOH, CFgCOOH, HCl, H ₂ S, 1,3- propandithiol and mixtures thereof. 34. chlorine, (II): Method for the synthesis of bacteriochlorins of the β, β ’-dihydroxy-meso-substituted or isobacteriochlorine of the formula wherein A is a ring having the structure: D is a ring having the structure: to R 8 are independently hydrogen, a lower alkyl group, a lower alkylcarboxylic acid, a zio ester esterified acidic group, keto, hydroxy, nitro, amino, or a group associated with another ring, ring substituent or meso substituent that forms a linked 5- or 6-membered ring and S 5 * to S 6 are H, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, which may be the same or different, provided that at least one general symbol up to does not represent H, characterized in that that includes the steps of: a. osmylation of a meso-substituted metalloporphyrin of formula (III) wherein M is a metal selected from the group consisting of Ni (II), Cu (II), Zn, Sn, Ge, Si, Ga, Al, Mn (III); Gd (III), In and Tc to form the eighth ester in the β, β´-position, b. disassembly of the metallized osmiate ester to give the corresponding β, β'-dihydroxy mesosubstituted chlorine, bacteriochlorine or isobacteriochlorine osmiate ester; and c. reduction of the demetalized ester osmate, wherein the ester osmate is converted to the corresponding β, β'-dihydroxy meso-substituted chlorine or bacteriochlorin of formula (II). 35. The method of claim 34 wherein M is Zn. 36. The method of claim 34, wherein at least one of A and D is a ring having the structure: 37. The method of claim 34, wherein said method comprises: wherein R 8 to R 8 are independently hydrogen, methyl, ethyl or lower alkyl esters. 38. The method of claim 34, wherein at least one of the moieties has the structure: Υ X X 'X' wherein X, Υ, X ', Υ' Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic ester, sulfonic acid or salt thereof, substituted sulfonic acid ester or an unsubstituted amino, cyano, nitro or biologically active group and Z 'is hydrogen or lower alkyl. The method of claim 27, wherein X, Υ, X ’, Y a and Z are a biologically active or amphiphilic enhancing moiety. 40. The method according to claim 34, characterized in that said Iy osmylation step comprises applying at least one equivalent per 0s0 ₄ mesosubstituted metalloporphyrin of formula (III) in the presence of a base. 41. The method according to claim 34, characterized in that in said step osmylačním and reacting the meso-substituted metalloporphyrin of formula (III) with 0s0 ₄ for from about 10 hours to about 5 days. 42. The method of claim 34, wherein said osmylation step a) is performed at room temperature and in the dark. 43. The method of claim 34, wherein said reducing step comprises treating said osmate ester with a reducing agent selected from the group consisting of H ₂ SO ₃ and H ₂ S. A method according to claim 34, characterized in that in said demetalate step the meso-substituted metalloporphyrin of formula (I) is treated with a demetalate selected from the group consisting of CH ₃ COOH, CF ₃ COOH, H ₂ SO ₄ , HCl, H ₂ s, 1,3-propanedithiol and mixtures thereof. 45. Process for the synthesis of β, β'-dihydroxy-meso-substituted chlorine, bacteriochlorines or isobacteriochlorine of formula (II): H where A is a ring having the structure: to R _g are independently hydrogen, lower alkyl, lower alkyl carboxylic acid /? e4c ester The amplified IF acidic group, keto, hydroxy, nitro, amino, or a group associated with another ring, ring substientem or meso substituent, forms a 5- or combined 6-membered ring a S 1 to H are substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, which may be the same or different, provided that at least one general symbol up to does not represent H, characterized in that it includes degrees: a. osmylation of a meso-substituted porphyrinogen compound of formula (IV): where A, D, RyazgaS ^ to Y are as defined above to form an eighth ester in the β, β 'position, b. reduction of the obtained ester osmate, wherein the ester osmate is converted to the corresponding β, β'-dihydroxy meso-substituted chlorine, bacteriochlorine or isobacteriochlorine compound of formula (II). 46. The process of claim 45 wherein Rf to Rg are independently hydrogen, methyl, ethyl or lower alkyl esters. 47. The method of claim 45, wherein at least one of the residues up to has a structure: YX wherein X, Υ, X ', Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or a salt thereof, carboxylic ester, sulfonic acid or salt thereof, substituted or unsubstituted sulfonic acid ester amino, cyano, nitro or a biologically active group, and Z 'is hydrogen or lower alkyl. 48. The method of claim 45, wherein said osmylating step aj comprises treating at least one equivalent of OsO2 meso-substituted metalloporphyrin of formula (IV) in the presence of a base. 49. The method of claim 45, wherein in said osmylation step, the meso-substituted porphyrinogen compound of formula (IV) is reacted with OsO2 for from about 10 hours to about 5 days. 50. The method of claim 45 wherein said osmylation step a) is carried out at room temperature and in the dark. 51; The method of claim 45, wherein the set in that during said reducing step comprises treating said osmate ester with a reducing agent selected from the group consisting of H2SO3 and _H2S